This multidimensional project is directed at identifying common etiologic pathways in three early onset dystonias, DYT1 (torsinA; TOR1A), DYT6 (Thap1; THAP1) and DYT25 (G-alpha-olf; GNAL). A three tier strategy will be employed to: 1) encompass candidates by expression profiling in human neurons derived from induced pluripotent stem cells (iPSCs) from patients (Aim 1, Bragg); 2) test candidate modifying genes in a living organism by RNAi screening of locomotion and dopamine metabolites in dtorsin-null Drosophila (Aim 2, Ito); and 3) evaluate implicated biologic processes in cultured neurons from a mouse model of DYT1 and neuronally differentiated iPSCs from patients (Aim 3, Breakefield). Our unifying hypothesis is that defects in these genes interfere with neurotransmitter receptor signaling in the brain, especially via acetylcholine and dopamine, with consequent compromise of synaptic plasticity known to be altered in DYT1 patients. In the case of DYT1 we hypothesize this results from compromise of the nuclear egress of ribonucleoprotein particles (RNPs) carrying mRNAs locally transcribed at synapses; for DYT6 from altered transcription of genes related to synaptic proteins, and for DYT25 from disruption of G coupled protein receptor signaling through dopamine receptors. Gene candidates will be further informed by molecular genetic analyses in dystonia patients (Project 1 and Core B) and by developmental and physiologic analyses in mouse models of these forms of dystonia (Projects 3). Insights into common pathways across dystonias will inform therapeutic strategies.